Kaposi's sarcoma (KS) is a tumor caused by infection with human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV) or KS agent. It was originally described by Moritz Kaposi, a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS-defining illnesses in the 1980s. It is characterized by proliferation of KSHV-infected spindle cells and abnormal neo-vasculature. KS most frequently involves the skin but may also involve the oral mucosa, lymph nodes, and viscera.
Before the AIDS epidemic, KS was rare in the United States. At that time, only about 2 new cases of KS were found for every million people in the United States each year. Most often, the types of KS that occurred were classic and transplant-related. With the AIDS epidemic, the rate of KS in this country increased more than 20 times—peaking at about 47 cases per million people (per year) in the early 1990s. Early in the AIDS epidemic, patients infected with HIV in the United States were estimated to have a 1 in 2 chance of developing KS. With new treatments for AIDS, KS has become less common in the United States, and it now occurs at a rate of about 6 cases per million people each year. It is still seen most often in people infected with HIV. In the United States, KS is much more common in men than in women, and it is rarely seen in children. It is also more common in African Americans than in whites in the United States. Transplant recipients are another group that gets KS. About 1 in 200 transplant patients in the United States gets KS. In certain instances such patients were already infected with KSHV before the transplant, but due to a healthy immune system, the virus was kept it in check. Following transplant, immunosuppression drugs can allow KS to develop. In areas of the world (such as Africa) where KSHV and HIV infection rates are high, both endemic and HIV-associated KS are seen, and KS occurs in men, women, and children. American Cancer Society website; http://www.cancer.org/cancer/kaposisarcoma/detailedguide/kaposi-sarcoma-what-is-key-statistics; information last revised Aug. 19, 2014.
The different types of KS are defined by the different populations it develops in, but the changes within the KS cells are very similar. Epidemic (AIDS-related) Kaposi sarcoma: The most common type of KS in the United States is epidemic or AIDS-related KS. This type of KS develops in people who are infected with HIV, the virus that causes AIDS. A person infected with HIV (that is, who is HIV-positive) does not necessarily have AIDS. The virus can be present in the body for a long time, often many years, before causing major illness. The disease known as AIDS begins when the virus has seriously damaged the immune system, which results in certain types of infections or other medical complications, including KS. When HIV damages the immune system, people who also are infected with a certain virus (the Kaposi sarcoma associated herpesvirus or KSHV) are more likely to develop KS. KS is considered an “AIDS defining” illness. This means that when KS occurs in someone infected with HIV, that person officially has AIDS (and is not just HIV-positive). In the United States, treating HIV infection with highly active antiretroviral therapy (HAART) has resulted in fewer cases of epidemic KS. Still, some patients develop symptoms of KS in the first few months of HAART treatment. For most patients with HIV, HAART can often keep advanced KS from developing. Still, KS can still occur in people whose HIV is well controlled with HAART. Once KS develops it is still important to continue HAART. In areas of the world where HAART is not easy to obtain, KS in AIDS patients can advance quickly.
Classic (Mediterranean) Kaposi sarcoma: Classic KS occurs mainly in older people of Mediterranean, Eastern European, and Middle Eastern heritage. Classic KS is more common in men than in women. Patients typically have one or more lesions on the legs, ankles, or the soles of the feet. Compared to other types of KS, the lesions in this type do not grow as quickly, and new lesions do not develop as often. The immune system of people with classic KS is not as weak as it is in those who have epidemic KS, but it may be weaker than normal. Getting older can naturally weaken the immune system a little. When this occurs, people who already have a KSHV (Kaposi sarcoma associated herpesvirus) infection are more likely to develop KS.
Endemic (African) Kaposi sarcoma: Endemic KS occurs in people living in Equatorial Africa and is sometimes called African KS. KSHV (Kaposi sarcoma associated herpesvirus) infection is much more common in Africa than in other parts of the world, so the risk of KS is higher. Other factors in Africa that weaken the immune system (such as malaria, other chronic infections, and malnutrition) also probably contribute to the development of KS, since the disease affects a broader group of people that includes children and women. Endemic KS tends to occur in younger people (usually under age 40). Rarely a more aggressive form of endemic KS is seen in children before puberty. This type usually affects the lymph nodes and other organs and can progress quickly. Endemic KS used to be the most common type of KS in Africa. Then, as AIDS became more common in Africa, the epidemic type became more common.
Iatrogenic (transplant-related) Kaposi sarcoma: When KS develops in people whose immune systems have been suppressed after an organ transplant, it is called iatrogenic, or transplant-related KS. Most transplant patients need to take drugs to keep their immune system from rejecting (attacking) the new organ. But by weakening the body's immune system, these drugs increase the chance that someone infected with KSHV (Kaposi sarcoma associated herpesvirus) will develop KS. Stopping the immune-suppressing drugs or lowering their dose often makes KS lesions go away or get smaller.
Kaposi sarcoma in HIV negative men who have sex with men: There have been reports of KS developing in men who have sex with men who are not infected with HIV. In this group, the cases of KS are often mild, similar to cases of classic KS.
For AIDS-related KS, most doctors use the AIDS Clinical Trials Group system. The AIDS Clinical Trials Group (ACTG) system for AIDS-related KS considers 3 factors: the extent of the tumor (T), the status of the immune system (I), as measured by the number of certain immune cells (CD4 cells) present in the blood, and the extent of involvement within the body or systemic illness (S). Under each major factor, there are 2 subgroups: either a 0 (good risk) or a 1 (poor risk).
T0 (good risk): Localized tumor. KS is only in the skin and/or the lymph nodes (bean-sized collections of immune cells throughout the body), and/or there is only a small amount of disease on the palate (roof of the mouth). The KS lesions in the mouth are flat rather than raised.
T1 (poor risk): The KS lesions are widespread. One or more of the following is present: edema (swelling) or ulceration (breaks in the skin) due to the tumor; extensive oral KS lesions that are nodular (raised) and/or lesions in areas of the mouth besides the palate (roof of the mouth); lesions of KS are in organs other than lymph nodes (such as the lungs, the intestine, the liver, etc.). Kaposi sarcoma in the lungs is a particularly bad sign.
I0 (good risk): CD4 cell count is 150 or more cells per cubic mm (mm3).
I1 (poor risk): CD4 cell count is lower than 150 cells per mm3.
S0 (good risk): No systemic illness present; all of the following are true: no history of opportunistic infections (infections that rarely cause problems in healthy people but affect people with suppressed immune systems) or thrush (a fungal infection in the mouth); no B symptoms lasting more than 2 weeks. B symptoms include: unexplained fever, night sweats (severe enough to soak the bed clothes), weight loss of more than 10% without dieting, diarrhea.
S1 (poor risk): Systemic illness present; one or more of the following is true: history of opportunistic infections or thrush; one or more B symptoms is present; KPS score is under 70; other HIV-related illness is present, such as neurological (nervous system) disease or lymphoma.
KSHV is also the causative agent of two B-cell lymphomas, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD), commonly seen in AIDS patients. There is currently no standard of care treatment for PEL, which is often lethal within 2 years. PEL cells latently infected with KSHV have constitutive up-regulation of NFkB and IRF4 and this is considered important in cell proliferation and disease pathogenesis of PEL.
An important component of the immune system is the killing of cells by cytotoxic T cells. Cytotoxic T cells recognize antigens such as peptides that are expressed bound to major histocompatibility complex class I (MHC-1) molecules, and expression of MHC-1 molecules is essential for an effective cytotoxic T cell response. This response is particularly important in the destruction of cells that produce abnormal proteins, including cells infected by viruses or bacteria, or tumor cells. Various viruses, including Kaposi sarcoma associated herpesvirus (KSHV), have evolved mechanisms to suppress expression of MHC-1, and this can enable them to evade killing by cytotoxic T cells. In addition, suppression of MHC-1 expression by tumors caused by KSHV or other viruses can blunt the immune response to the tumors, allowing them to develop and then facilitating their growth. In the case of KSHV, much of the suppressing of MHC-1 is the result of two lytic KSHV genes, K3 and K5, that act as ubiquitin ligases.
Despite antiretroviral therapy (ART), people with HIV continue to exhibit immune deficits including failure to fully reconstitute CD4 T-cell numbers and function, resulting in increased risks of tumors and infections and reduced response to vaccination. There still exists an unmet need for agents for the treatment of KS and other KSHV-induced cancers which are deliverable orally, accessible in resource-limiting settings, and/or work long term for relapsing diseases.
Pomalidomide is an immunomodulatory compound that has a number of actions, including an anti-tumor effect in multiple myeloma and an increase in T cell responsiveness. Lenalidomide is another immunomodulatory compound that is approved for use in multiple myeloma and also has been shown to be active in certain lymphomas. It has been found that one basis for the activity of immunomodulatory compounds is their binding to cereblon, a component of the U3 ubiquitin ligase. See Ishido et al., J. Virol. 2000, 74:5300-9; Paulson et al., Virology 2001, 288:369-78; Horst et al., Current opinion in immunology 2011, 23:96-103. Pomalidomide augments T cells responsiveness and proliferation by several mechanisms, leading to increased production of IL-2 and interferon-γ (IFN-γ). It enhances CD4- and CD8-positive T cell co-stimulation, associated with increased tyrosine phosphorylation of CD28 on T cells and activation of the PI3-K signaling pathway, and enhances transcriptional activity of activated protein-1 (AP-1), a driver of IL-2. This T cell reprogramming is mediated at least in part by induction of the transcription factor T-bet. In addition, T regulatory (Treg) cell expansion and FOXP3 expression on Tregs are inhibited without affecting survival or apoptosis, or Treg expression of IL-10 or TGF-β. Th1 cytokine production is also enhanced
There is a substantial unmet need for novel KS therapies. There is a lack of effective oral agents; chronic administration of cytotoxic agents is poorly tolerated, in part due to hematotoxicity; and cumulative anthracyclines increase cardiotoxicity risk. The latter considerations are significant as KS commonly recurs and patients often require treatment, at least intermittently, for years. Also, with the exception of ART, no treatment is readily deliverable in resource-limited areas such as sub-Saharan Africa where KS burden is greatest. Accordingly, provided herein is a solution to these and other problems in the art.